Chronic therapy with the beta1 selective partial agonist xamoterol is not associated with the tolerance seen with agonists of greater intrinsic activity. In order to investigate whether this could be explained by the effect of xamoterol on the in vivo regulation of cardiac beta-adrenoceptors, 2 studies have been performed. 40 right atrial biopsies were obtained from 55 patients prospectively randomised in a double blind fashion to receive either xamoterol or the beta1 selective antagonist atenolol (previously shown to upregulate beta1-adrenoceptors and enhance beta2 mediated responses) for at least 5 weeks prior to treatment groups but basal and stimulated adenylate cyclase activities were significantly lower in the xamoterol group. Ethical constraints prevented the inclusion of a placebo control group, but data from a small group of patients taking neither drug suggested that the xamoterol group had higher adenylate cyclase activities than patients not treated with this drug. Thus xamoterol did not downregulate human cardiac beta-adrenoceptors and is unlikely to have desensitised adenylate cyclase responses. The lack of a placebo control group and the inability to demonstrate the coupling of beta1-adrenoceptors to adenylate cyclase limited the human study. A complementary rat model was therefore used. Rats were infused for 6 days with either xamoterol or the full agonist isoprenaline using sham operated animals for control. Unlike isoprenaline, xamoterol infusion did not downregulate cardiac beta-adrenoceptors, and although it selectively densensitised beta1 mediated stimulation of adenylate cyclase, it did so significantly less than isoprenaline which also desensitised beta2-adrenoceptor responses. Thus xamoterol desensitised beta-adrenoceptor mediated stimulation of adenylate cyclase significantly less than isoprenaline. The results of both studies may explain the observed lack of tolerance to xamoterol therapy in the treatment of heart failure.